Recent technological advances have led to the isolation of multiple pluripotent cell lines derived from embryonic and adult tissues and from multiple mammalian species. These new sources of pluripotent cells provide novel tools that offer multiple rewards for basic and clinical research. The aim of this study is to create a novel strategy to generate rodents derived solely from pluripotent cells. Our proposal is based on the creation of mosaic embryos composed of pluripotent cells and genetically defective embryos. Using this strategy, we force the generation of animals composed solely of the donor pluripotent cells. This strategy will facilitate the generation of mice and rats to model human disease. It will also advance our understanding of mammalian gene function and the identification of gene products of therapeutic value. PUBLIC HEALTH RELEVANCE: The study proposes a new strategy for rodent cloning using pluripotent cells. This new technology will facilitate the generation of transgenic mice and rats models for human disease. In addition, it will provide genetic tools for the functional annotation of the mouse genome, an enterprise with the potential to elucidate gene function and identification of gene products with therapeutic value.